Objective To investigate the effects of indirubatin derivative E804 on proliferation and migration of non-small cell lung cancer(NSCLC)A549 cells,and to elucidate the possible mechanism of Nrf2-HO-1/GPX4 pathway.Methods Lung cancer A549 cells were used as the cell model.The proliferation and migration of differ-ent specific inhibitors(Nec-1,CQ,Z-VAD,DFO,Fer-1 and Lip-1)in 0,10 μmol/L E804 and 10 μmol/L E804+groups were observed by MTT and cell scratch assay.The contents of reactive oxygen species(ROS)were de-tected by DCFH-DA fluorescence probe method,the contents of Fe2+were detected by colorimetric method,the contents of reduced glutathione(GSH)were detected by spectrophotometry,and the contents of malondialdehyde(MDA)were detected by micromethod.The expression levels of SLC7A11,Transferrin,GPX4,SLC40A1,Nrf2 and HO-1 were detected by Western blot in cells of 0,2.5,5 and 10 μmol/L E804 groups.Results Compared with the control group(0 μmol/L E804),2.5,5 and 10 μmol/L E804 significantly increased intracellular ROS,Fe2+and MDA levels,and decreased intracellular GSH content(P＜0.01).Meanwhile,the expression levels of SLC7A11,GPX4,SLC40A1,Nrf2 and HO-1 significantly decreased(P＜0.01),and the expression level of Transferrin increased(P＜0.05).Compared with the 10 μmol/L E804 group alone,the apoptosis inhibitor(Z-VAD)group and the ferroptosis inhibitor(DFO,Fer-1 and Lip-1)group could significantly reverse the inhibition of proliferation and migration of A549 cells by 10 μmol/L E804(P＜0.01).Conclution E804 can induce ferrop-tosis and inhibit the proliferation and migration of A549 cells,which may be related to the inhibition of Nrf2-HO-1/GPX4 pathway.

Skeletal muscle injury is a common disease in clinical practice,and an in-depth understanding of its repair mechanisms is crucial for the development of effective therapeutic strategies.This paper focuses on the key role of TGF-β in skeletal muscle injury repair,introduces the diversity of its family members and signaling pathways,explores the expression and regulation part of TGF-β after skeletal muscle injury,analyzes its early expression dynamics and regulatory factors,and thoroughly investigates the effects of TGF-β on skeletal muscle repair,revealing its inflammatory regulation,cellular activation and proliferation as well as fibrosis.Key role.Special attention was paid to its mechanism of action in muscle regeneration and its regulatory mechanism at the cellular level.In addition,the potential clinical applications of TGF-β in the repair of skeletal muscle injury were discussed,and the development and application of it as a therapeutic target and modulator were explored.However,controversies and shortcomings still exist in the current study,such as the dual roles of TGF-β and the impact of individual differences on treatment.Future research directions should include digging deeper into the details of signaling pathways and biomarker discovery.By overcoming these challenges,the potential clinical application of TGF-β in skeletal muscle injury repair is expected to usher in new breakthroughs and provide patients with more individualized and effective treatment strategies.

Objective This study aimed to investigate the effects of P.odoratum extract on lactase activity and microflora diversity in mice with bacterial dysbacteriosis.Methods SPF male BALB/c mice were randomized into 4 groups:control,model,P.odoratum extract low dose(1.56 g·kg-1·d-1)and high dose(3.12 g·kg-1·d-1)treatment group.There were 8 mice in each group(5 in the blank group).In addition to the control group,after 7 days of intragastric administration of mixed antibiotics,the administration groups were given P.odoratum extract for 7 days,and the control group and the model group were given the same amount of sterile water.The changes of diarrhea,body weight and food intake of mice were recorded.The colon HE staining sections,ZO-1 protein,IL-6 expression,and serum LPS concentration were detected.Feces were collected for lactase activity and microbial diversity determination with 16S rRNA high-throughput sequencing technology.Results After 7 days of antibiotic intervention,compared with the control group,the mice in the model group had soft stool,weight loss,reduced food intake,and significantly reduced intestinal flora diversity.At the 14th day,in the model group,ulceration accompanied by slight interstitial congestion and edema was seen in the colon,ZO-1 expression was significantly reduced,IL-6 expression was significantly increased,serum LPS was significantly increased,lactase activity was significantly reduced,and intestinal flora diversity was still lower compared with the control group.After 7 days of administration,compared with the model group,P.odoratum reduced the diarrhea rate of mice,promoted a recovery of body weight and food intake,downregulated pathological colon tissue damage,significantly increased ZO-1 protein expression,and reduced colon factor IL-6 and serum LPS concentration.In addition,P.odoratum can significantly up-regulate lactase activity and improve the community richness and diversity of dysbacteriosis mice.It is shown that three phyla(up-regulated Firmicutes,down-regulated Proteobacteria and Bacteroidetes)and seven genera(up-regulated Rikenellaceae_RC9_gut_group,Rikenella,Colidextribacter,norank_f__Lachnospiraceae,norank_f__Oscillospiraceae,and Lachnospiraceae_NK4A136_group,down-regulated Alloprevotella),the abundance of which was significantly correlated with body weight and lactase activity,serum LPS,and colon factor IL-6.Conclusion P.odoratum can alleviate the gut barrier injury and dysfunction caused by antibiotic induced dysbiosis,and its mechanism may be achieved by regulating microflora structure.

Objective:Congenital hyperinsulinemia is a heterogeneous disorder characterized by severe hypoglycemia due to dysregulated insulin secretion. Sixteen genes have been reported to be associated with congenital hyperinsulinemia. In this study, whole exome sequencing was performed on a patient with obesity, hyperinsulinemia, and postprandial hypoglycemia to further explore its genetic etiology.Methods:The clinical data and peripheral blood of a patient with hyperinsulinemia and his family members were collected. Genomic DNA was extracted from the peripheral blood. Sanger sequencing and pedigree verification were performed on the pathogenic variants filtered by whole-exome sequencing. The function of the mutation sites was analyzed by bioinformatics software.Results:The proband presented with obesity, hyperinsulinemia, and postprandial hypoglycemia, but without exercise-induced hypoglycemia. A heterozygous SCL16A1 gene c. 1259A>G(p.K420R) mutation was identified in the proband. Co-segregated analysis showed that the c. 1259A>G mutation was also found in his father and brother, who had obesity and hyperinsulinemia, which was consistent with autosomal dominant inheritance. The mutation c. 1259A>G was predicted to be pathogenic by the MutationTaster, FATHMM-MKL, PolyPhen2, and CADD programs, and has not been reported in HGDM database yet, which was considered to be a novel mutation.Conclusion:This study reported a patient with hyperinsulinemia caused by a new mutation of SCL16A1 gene, which expanded our understanding of the pathogenic mutation spectrum of hyperinsulinemia.

Liver transplantation is a vital treatment for end-stage liver disease. However, the shortage of donor livers has limited the development of liver transplantation. How to expand the source of donor livers has become a challenge in the academic community. In recent years, the proportion of donors with non-alcoholic fatty liver disease (NAFLD) has been increased. Rational use of steatotic donor livers is a feasible approach to expand the donor pool. Cold ischemia injury during donor liver preservation before liver transplantation increases the risk of postoperative organ dysfunction. Therefore, it is of significance to unravel the mechanism and intervention measures of cold ischemia injury of steatotic donor livers. Cold ischemia injury of steatotic donor livers is characterized as the damage of mitochondria, lysosomes and endoplasmic reticulum at the organelle level, and up-regulated expression of adenosine monphosphate activated protein kinase (AMPK), aldehyde dehydrogenase 2 (ALDH2) and heme oxygenase (HO)-1 at the protein level. In this article, the research progresses on cold ischemia injury of steatotic donor livers and relevant intervention measures were reviewed.

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl₄. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6C^high macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl₄-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl₄-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

[This corrects the article DOI: 10.1016/j.apsb.2022.06.009.].

【Objective】 To analyze the composition of urinary calculi in Longnan, Gansu province, and the relationship between the composition and clinical characteristics of patients, so as to provide reference for the prevention and treatment of this disease. 【Methods】 The composition of 500 cases of urinary calculi hospitalized in our department during Apr. 2021 and Feb.2023 were analyzed using the infrared spectrum stone composition analyzer. The clinical characteristics of the patients were evaluated and analyzed. 【Results】 The male-to-female ration of patients was 2.70∶1. Most patients aged 21 to 60 years (437, 87.4%). Most cases were ureteral calculi (72.8%), followed by renal calculi (22.2%), and bladder calculi (5.0%). There were 166 cases of calcium oxalate calculi, 293 cases of calcium oxalate + carbonated apatite calculi, 24 cases of calcium oxalate + carbonated apatite + hydroxyl apatite calculi, 4 cases of calcium oxalate + calcium bicarbonate calculi, 7 cases of urate calculi, 6 cases of carbonated apatite + struvite calculi. Oxalate calculi were the most common in all age groups, and urate calculi were the most common in the 21 to 40 age group. Calcium oxalate calculi were most common in the ureter (127, 76.5%), significantly higher than in other sites (χ²=3.222, P=0.020). Calcium oxalate + calcium hydrogen phosphate calculi was the least common in the bladder, significantly different from the other parts (χ²=2.092, P=0.037). Magnesium ammonium phosphate hexahydrate and/or calcium carbonate or calcium oxalate calculi were the most common in the kidney (50.0%), significantly different from the other parts (χ²=9.448, P=0.007). 【Conclusion】 In Longnan area, the incidence of urinary calculi is significantly higher in male than in female. Ureteral calculi are mainly composed of calcium oxalate + carbonated apatite and calcium oxalate. According to different risk factors, individual prevention programs should be developed.

Objective To evaluate the impact of customized rehabilitation exercise plans based on the results of cardiopulmonary exercise test(CPET)on cardiac function and prognosis in patients with chronic heart failure(CHF).Methods A total of 52 CHF patients admitted to Chengde Central Hospital from February 2020 to September 2021 were selected as the study subjects,and the patients were divided into observation group and control group according to the principle of randomized controlled study,with 26 cases in each group.The control group received rehabilitation treatment excluding exercise.The observation group was given routine rehabilitation treatment and high-intensity rehabilitation exercise plans based on CPET guidance.Above anaerobic threshold Δ50%power was exercise intensity,exercise time was 30 minutes/day,4 days/week,and intervention period was 12 weeks.Before and 12 weeks after intervention,CPET functional indicators,serum brain natriuretic peptide(BNP),left ventricular ejection fraction(LVEF),left ventricular end-diastolic diameter(LVEDD),and 6-minute walking distance(6MWD)were measured.The Minnesota CHF quality of life questionnaire(LiHFe)was used to evaluate patient's quality of life,readmission rate and cardiogenic mortality within 1 year of follow-up,and univariate and multivariate Logistic regression analysis was used to analyze factors affecting readmission of CHF patients.Results ① Cardiopulmonary function indicators:there was no statistically significant difference in the anaerobic threshold,peak oxygen uptake,and peak oxygen pulse of CPET functional indicators before and after intervention in the control group,after intervention,the CPET functional indicators in the observation group were significantly higher than those before intervention,and the above indexes in the observation group were significantly higher than those of the control group[anaerobic threshold(mL·min-1·kg-1):10.77±1.40 vs.9.59±1.11,anaerobic threshold(%ped):78.95±11.39 vs.70.09±6.48,peak oxygen uptake(mL·min-1·kg-1):15.63±1.36 vs.14.27±1.72,peak oxygen uptake(%ped):72.42±6.91 vs.63.41±7.31,peak oxygen pulse(mL/order):11.38±1.29 vs.9.05±1.64,peak oxygen pulse(%ped):90.23±10.16 vs.80.53±6.73,all P＜0.05].②Serum indicators,cardiac function indicators,exercise ability indicators,and quality of life evaluation:there was no statistically significant difference in serum indicators BNP,cardiac function indicators LVEDD,LVEF,exercise ability indicators 6MWD,and quality of life LiHFe scores between the two groups before intervention.After intervention,BNP and LiHFe scores were significantly reduced compared with before intervention,while LVEF and 6MWD were both increased compared with before intervention,and the changes of the above indexes in the observation group were more significant than those in the control group[BNP(ng/L):313.25±77.91 vs.445.89±110.67,LVEF:0.41±0.08 vs.0.37±0.06,6MWD(m):495.62±91.35 vs.416.04±65.29,LiHFe score:23.27±6.02 vs.29.50±4.61,all P＜0.05].③ Prognostic follow-up:the readmission rate within 1 year in the observation group was significantly lower than that in the control group(23.08%vs.53.85%),and there was no statistically significant difference in the mortality rate of cardiogenic diseases between the two groups.④Logistic univariate analysis showed that hyperlipidemia,New York Heart Association(NYHA)grading,BNP,and rehabilitation exercise were factors that affect the prognosis of CHF patients[odds ratio(OR)and 95%confidence interval(95%CI)were 0.098(0.019-0.494),0.069(0.016-0.294),1.018(1.007-1.029),and 3.889(1.178-12.841),respectively,all P＜0.05].Multivariate analysis showed that after adjusting for other factors,hyperlipidemia,NYHA grading,and BNP were risk factors affecting the prognosis of CHF patients(OR and 95%CI were 0.068(0.007-0.687),0.048(0.005-0.415),1.016(1.002-1.030),respectively,with P＜0.05],the use of rehabilitation exercise therapy was a protective factor affecting the prognosis of CHF patients[OR and 95%CI were 11.179(1.135-10.124),P＜0.05].Receiver operator characteristic curve(ROC curve)analysis showed that hyperlipidemia,NYHA grading,BNP,rehabilitation exercise therapy,and combined testing all had predictive value for the patient's prognosis(all P＜0.05),and the prediction value of joint detection was the highest,with the area under the ROC curve(AUC)=0.984 and P = 0.000.Conclusion Developing a high-intensity individualized cardiac exercise rehabilitation plan under the guidance of CPET can help improve the cardiopulmonary function,cardiac function,and quality of life of CHF patients,which is of great benefit for improving the long-term prognosis of CHF patients and has high safety.